title: The effect of polyoxyethylene polymers on the transport of ranitidine in Caco-2 cell monolayers.
abstract: Previous in vivo studies using PEG 400 showed an enhancement in the bioavailability of ranitidine. This study investigated the effect of PEG 200, 300 and 400 on ranitidine transport across Caco-2 cells. The effect of PEG polymers (20%, v/v) on the bi-directional flux of (3)H-ranitidine across Caco-2 cell monolayers was measured. The concentration dependence of PEG 400 effects on ranitidine transport was also studied. A specific screen for P-glycoprotein (P-gp) activity was used to test for an interaction between PEG and P-gp. In the absence of PEG, ranitidine transport showed over 5-fold greater flux across Caco-2 monolayers in the secretory than the absorptive direction; efflux ratio 5.38. PEG 300 and 400 significantly reduced this efflux ratio (p<0.05), whereas PEG 200 had no effect (p>0.05). In concordance, PEG 300 and 400 showed an interaction with the P-gp transporter, whereas PEG 200 did not. Interestingly, with PEG 400 a non-linear concentration dependence was seen for the inhibition of the efflux ratio of ranitidine, with a maxima at 1%, v/v (p<0.05). The inhibition of ranitidine efflux by PEG 300 and 400 which interact with P-gp provides a mechanism that may account for the observations of ranitidine absorption enhancement by PEG 400 in vivo.
authors.affiliation: Department of Pharmaceutics, The School of Pharmacy, University of London, 29-39 Brunswick Square, London, WC1N 1AX, UK.
authors.forename: Diane A I
authors.initials: DA
authors.lastname: Ashiru-Oredope
authors.forename: Nilesh
authors.initials: N
authors.lastname: Patel
authors.forename: Ben
authors.initials: B
authors.lastname: Forbes
authors.forename: Rajesh
authors.initials: R
authors.lastname: Patel
authors.forename: Abdul W
authors.initials: AW
authors.lastname: Basit
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001692:Biological Transport; D018938:Caco-2 Cells; D005079:Excipients / Q000737:chemistry*; D006635:Histamine H2 Antagonists / Q000493:pharmacokinetics; D006801:Humans; D011092:Polyethylene Glycols / Q000737:chemistry*; D011899:Ranitidine / Q000493:pharmacokinetics*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005079:Excipients; D006635:Histamine H2 Antagonists; D011092:Polyethylene Glycols; D011899:Ranitidine